Insulin-dependent diabetes mellitus (IDDM) or autoimmune diabetes is a polygenic, multifactorial, autoimmune disease heralded by T cell infiltration of the pancreatic islets of Langerhans (insulitis) and the β progressive T cell-mediated destruction of insulin-producing cells (Bach, 1994; Atkinson and Maclaren, 1994; Tisch and McDevitt, 1996).
Non-obese diabetic (NOD) mice are susceptible to the development of IDDM and are an accepted model for the development of autoimmune IDDM in humans.
CD4+ T helper cells are required for the adoptive transfer of IDDM into recipient neonatal NOD mice or immunodeficient NOD.Scid mice (Bendelac et al., 1987, Christianson et al., 1993; Rohane et al., 1995). Cooperation between CD4+ and CD8+ T cells is required to initiate IDDM, and islet β cell destruction is CD4+ T cell-dependent (Haskins and McDuffie, 1990; Wang et al., 1991). Current evidence suggests that the CD4+ effector cells of IDDM in NOD mice at Th1 cells which secrete IL-2, IFN-γ and TNF-α and that the regulatory CD4+ cells are Th2 cells which secrete IL-4, IL-5, IL-6, IL-10 and IL-13 (Rabinovitch, 1994; Liblau et al., 1995; Katz et al., 1995).
NOD mouse T cells show proliferative hyporesponsiveness to T cell receptor (TCR) stimulation and this hyporesponsiveness may be causal to the development of IDDM.
It has been shown that, beginning at 3-5 weeks of age, T cell receptor (TCR) ligation in NOD mice induces the proliferative hyporesponsiveness of NOD thymic and peripheral T cells, which is mediated by reduced IL-2 and IL-4 production (Zipris et al., 1991; Rapoport et al., 1993a; Jaramillo et al., 1994).
Decreased IL-4 production by human T cells from patients with new onset IDDM has also been demonstrated recently (Berman et al., 1996). Whereas addition of IL-4, a Th2-type cytokine, potentiates Il-2 production and completely restores NOD T cell proliferative responsiveness, addition of IL-2, a Th1-type cytokine, even at high concentrations, only partially restores NOD T cell responsiveness. These findings suggest that Th2 cells may be compromised in function to a greater extent than Th1 cells in NOD mice, and raise the possibility that Th2 cells require a higher threshold of activation than Th1 cells in these mice. IL-4 not only restores NOD T cell responsiveness in vitro, but prevents insulitis and IDDM when administered in vivo to prediabetic NOD mice (Rapoport et al., 1993a) or when transgenically expressed in pancreatic β cells (Mueller et al., 1996).
The proliferative hyporesponsiveness of regulatory Th2 cells in NOD mice may favour a Th1 cell-mediated environment in the pancreas of these mice, and lead to a loss of immunological tolerance to islet β cell autoantigens. This is consistent with the notion that restoration of the balance between Th1 and Th2 cell function may prevent IDDM (Rabinovitch, 1994; Liblau et al., 1995; Arreaza et al., 1996).
Optimal T cell activation requires signalling through the TCR and the T cell CD28 costimulatory receptor (CD28) (June et al., 1994; Bluestone, 1995; Thompson, 1995). Crosslinking of the TCR/CD3 complex in the absence of a CD28-mediated costimulatory signal induces a proliferative unresponsiveness that is mediated by the inability of T cells to produce IL-2 (Jenkins et al., 1991). CD28 costimulation prevents proliferative unresponsiveness in Th1 cells by augmenting the production of IL-2, which in turn promotes IL-4 secretion by T cells (Seder et al., 1994). The costimulatory pathway of T cell activation involves the interaction of CD28 with its ligands B7-1 and B7-2 on an antigen presenting cell (APC), with B7-2 considered as the primary ligand for CD28 (Linsley et al.,1990; Freeman et al., 1993; Lenschow et al., 1993; Freeman et al., 1995). When costimulation is blocked by either CTLA4-Ig or by anti-B7-1 or anti-B7-2 monoclonal antibodies (mAbs), differential effects on the incidence of various autoimmune diseases (e.g. IDDM) and on the development of Th1 and Th2 cells are observed (Kuchroo et al., 1995; Lenschow et al., 1995). Furthermore, in vivo studies have demonstrated that the generation of Th2 cells is more dependent upon the CD28-B7 pathway than the priming of Th1 cells, and suggest that the development of Th subsets in vivo may be influenced by limited CD28-B7 costimulation (Corry et al., 1994; Lu et al., 1994). Analyses of the development of human Th2 cells have yielded results similar to those observed in the mouse (King et al., 1995; Kalinski et al., 1995; Webb and Feldman, 1995). Interactions between CD28 and its B7-2 ligand are essential for the costimulation of an IL-4-dependent CD4+ T cell response, and IL-4 increases B7-1 and B7-2 surface expression on certain professional APCs (eg. Langerhans cells) and B cells (Freeman et al., 1995; Kawamura et al., 1995; Stack et al., 1994). Thus, failure to activate NOD thymocytes and peripheral T cells sufficiently may be due to functional and/or differentiation defects in NOD APCs, which remain able to optimally activate islet β cell autoreactive CD4+ effector T cells, but not regulatory CD4+ T cells (Serreze et al., 1988; Serreze et al., 1993). Functional defects that compromise antigen presentation by NOD APCs, such as deficient CD28 costimulation, may lower their ability to stimulate regulatory Th2 cells without compromising their ability to stimulate autoreactive effector Th1 cells.
Proliferative hyporesponsiveness of T cells has been observed in other autoimmune diseases such as multiple sclerosis and myasthenia gravis.
If proliferative hyporesponsiveness of T cells in autoimmune disease could be overcome, it might be possible by that means to prevent the development of autoimmune diseases.